R. Hunter - Academia.edu (original) (raw)

Papers by R. Hunter

AJP: Cell Physiology, 2006

tal muscle atrophy is associated with a marked and sustained activation of nuclear factor-B (NF-B... more tal muscle atrophy is associated with a marked and sustained activation of nuclear factor-B (NF-B) activity. Previous work showed that p50 is one of the NF-B family members required for this activation and for muscle atrophy. In this work, we tested whether another NF-B family member, c-Rel, is required for atrophy. Because endogenous inhibitory factor B␣ (IB␣) was activated (i.e., decreased) at 3 and 7 days of muscle disuse (i.e., hindlimb unloading), we also tested if IB␣, which binds and retains Rel proteins in the cytosol, is required for atrophy and intermediates of the atrophy process. To do this, we electrotransferred a dominant negative IB␣ (IB␣⌬N) in soleus muscles, which were either unloaded or weight bearing. IB␣⌬N expression abolished the unloading-induced increase in both NF-B activation and total ubiquitinated protein. IB␣⌬N inhibited unloading-induced fiber atrophy by 40%. The expression of certain genes known to be upregulated with atrophy were significantly inhibited by IB␣⌬N expression during unloading, including MAFbx/atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, and cathepsin L, suggesting these genes may be targets of NF-B transcription factors. In contrast, c-Rel was not required for atrophy because the unloading-induced markers of atrophy were the same in c-rel Ϫ/Ϫ and wild-type mice. Thus IB␣ degradation is required for the unloading-induced decrease in fiber size, the increase in protein ubiquitination, activation of NF-B signaling, and the expression of specific atrophy genes, but c-Rel is not. These data represent a significant advance in our understanding of the role of NF-B/IB family members in skeletal muscle atrophy, and they provide new candidate NF-B target genes for further study.

AJP: Cell Physiology, 2006

tal muscle atrophy is associated with a marked and sustained activation of nuclear factor-B (NF-B... more tal muscle atrophy is associated with a marked and sustained activation of nuclear factor-B (NF-B) activity. Previous work showed that p50 is one of the NF-B family members required for this activation and for muscle atrophy. In this work, we tested whether another NF-B family member, c-Rel, is required for atrophy. Because endogenous inhibitory factor B␣ (IB␣) was activated (i.e., decreased) at 3 and 7 days of muscle disuse (i.e., hindlimb unloading), we also tested if IB␣, which binds and retains Rel proteins in the cytosol, is required for atrophy and intermediates of the atrophy process. To do this, we electrotransferred a dominant negative IB␣ (IB␣⌬N) in soleus muscles, which were either unloaded or weight bearing. IB␣⌬N expression abolished the unloading-induced increase in both NF-B activation and total ubiquitinated protein. IB␣⌬N inhibited unloading-induced fiber atrophy by 40%. The expression of certain genes known to be upregulated with atrophy were significantly inhibited by IB␣⌬N expression during unloading, including MAFbx/atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, and cathepsin L, suggesting these genes may be targets of NF-B transcription factors. In contrast, c-Rel was not required for atrophy because the unloading-induced markers of atrophy were the same in c-rel Ϫ/Ϫ and wild-type mice. Thus IB␣ degradation is required for the unloading-induced decrease in fiber size, the increase in protein ubiquitination, activation of NF-B signaling, and the expression of specific atrophy genes, but c-Rel is not. These data represent a significant advance in our understanding of the role of NF-B/IB family members in skeletal muscle atrophy, and they provide new candidate NF-B target genes for further study.